The number of people with mood disorders, such as bipolar disorder with or without psychotic features, mania or mixed episodes is increasing every year for numerous reasons. Since the period of 1950, tricyclic antidepressant drugs (e.g., imipramine, desipramine, amitriptyline, etc.) have been developed that act to inhibit monoamine reuptake. They are frequently used for treating patients suffering from mood disorders. However, these drugs have side-effects, such as the following: dry mouth, hazy eyes, dysuria, constipation, recognition disturbance and the like due to anticholinergic activity; cardiovascular side-effects such as, orthostatic hypotension, tachycardia and the like on the basis of α1-adrenoreceptor antagonist activity; side-effects such as, sedation, increase in the body weight and the like on the basis of histamine-H1 receptor antagonist activity.
Although the mood disorders including bipolar disorder with or without psychotic features, mania or mixed episodes are heterogeneous diseases, and the causes of these diseases are not fully understood, it is likely that the abnormalities of the monoaminergic central nervous system caused by serotonin, norepinephrine and dopamine and the like, and the abnormality of various hormones and peptides as well as various stressors are causes of depression and various other mood disorders (Kubota Masaharu et al.: “RINSHOU SEISHIN IGAKU” Vol. 29, pp 891-899, (2000)). For these reasons, even though mood stabilizer drugs, such as lithium, valproic acid, divalproex sodium, carbamazapine, oxcarbamazapine, zonisamide, lamotragine, topiramate, gabapentin, levetiracetam and clonazepam have been used, these drugs are not always effective in treating all patients.
New therapeutic trials involve proposed combined therapies using an atypical antipsychotic drug, such as olanzepine or quetiapine, which are agents for treating schizophrenia (anti-psychotic drug), together with mood stabilizing drug such as valproate, lithium or divalproex ((Arch. Gen. Psychiatry, 2002 January 59:1):62-69; J Am Acad Child Adolesc Psychiatry 2002 October; 41(10) :1216-23.)
Further, commercially available atypical antipsychotic drugs have significant problems relating to their safety. For example, clozapine, olanzapine and quetiapine increase body weight and enhance the risk of diabetes mellitus (Newcomer, J. W. (Supervised Translated by Aoba Anri): “RINSHOU SEISHIN YAKURI” Vol. 5, pp 911-925, (2002), Haupt, D. W. and Newcomer, J. W. (Translated by Fuji Yasuo and Misawa Fuminari): “RINSHOU SEISHIN YAKURI” Vol. 5, pp 1063-1082, (2002)). In fact, urgent safety alerts have been issued in Japan relating to hyperglycemia, diabetic ketoacidosis and diabetic coma caused by olanzapine and quetiapine, indicating that these drugs were subjected to dosage contraindication to the patients with diabetes mellitus and patients having anamnesis of diabetes mellitus. Risperidone causes increases serum prolactin levels and produces extrapyramidal side effects at high dosages. Ziprasidone enhances the risk of severe arrhythmia on the basis of cardio-QTc prolongation action. Further, clozapine induces agranulocytosis, so that clinical use thereof is strictly restricted (van Kammen, D. P. (Compiled under Supervision by Murasaki Mitsuroh) “RINSHOU SEISHIN YAKURI” Vol. 4, pp 483-492, (2001)).
Accordingly what is needed are new compositions useful for treating mood disorders, particularly bipolar disorder with or without psychotic features, mania or mixed episodes, which are efficacious and do not cause the deleterious side effects associated with prior art compounds.